The importance of the cholinergic system in memory function was first recognized because the memory impairment characteristic of Alzheimers disease was associated with the loss of large cholinergic neurons of the basal forebrain and pathophysiology of the entorhinal/perirhinal, or rhinal cortex. We first demonstrated a cholinergic contribution to visual recognition memory in a series of studies showing that this function could be enhanced and impaired, respectively, by systemic administration of the cholinergic agonist, physostigmine, and the cholinergic antagonist, scopolamine. More recently we made infusions of a selective cholinergic immunotoxin, which lead to cholinergic deafferentation of the rhinal cortex and yielded recognition deficits of the same magnitude as those produced by excitotoxic lesions of this region. This, to date, is the most direct demonstration that cholinergic activation of the rhinal cortex is essential for storing of visual representations and thereby enabling their later recognition. In addition, substantial recognition memory deficits have been found following local microinfusions of the non-selective muscarinic antagonist scopolamine into the rhinal cortex providing further evidence that acetylcholine serves an important role in perirhinal cortical function and recognition memory. Scopolamine, however, includes antagonists of both m1 and m2 receptor subtypes. To assess the effects of selective blockade of muscarinic receptor subtypes, we infused either the m1-selective antagonist pirenzepine, or the m2-selective antagonist methoctramine directly into the rhinal cortex of animals performing one-trial visual recognition, and compared these scores with those following infusions of equivalent volumes of saline. Compared with control performance following saline infusions, injections of pirenzepine, but not of methoctramine, significantly impaired recognition accuracy. These findings suggest that m1 and m2 receptor subtypes in the perirhinal cortex have functionally dissociable roles, and that visual recognition memory is critically dependent on the m1 receptor subtype. In contrast to what we know about recognition memory and the importance of the rhinal cortex and cholinergic activity, the monkeys ability to learn a set of visual discriminations presented concurrently just once a day on successive days (24-h ITI task) is based on habit formation, which is known to rely on a visuo-striatal circuit and to be independent of the visuo-rhinal processing stream. Consistent with this dissociation, we recently found that performance on the 24-h ITI task is impaired by a striatal-function blocking agent, the dopaminergic antagonist haloperidol, and not by the rhinal-function blocking agent, the muscarinic cholinergic antagonist scopolamine. In a follow-up study we trained monkeys on a short-ITI form of concurrent visual discrimination learning, one in which a set of stimulus pairs is repeated not only across daily sessions but also several times within each session. Asymptotic discrimination learning rates in the non-drug condition were reduced by half, from ∼11 trials/pair on the 24-h ITI task to ∼5 trials/pair on the 4-min ITI task, and this faster learning was impaired by systemic injections of either haloperidol or scopolamine. The results suggest that in the version of concurrent discrimination learning used here, the short ITIs within a session recruit both visuo-rhinal and visuo-striatal circuits, and that the final performance level is driven by both cognitive memory and habit formation working in concert.

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U.S. National Institute of Mental Health
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